Methods of Testosterone Supplementation for Men and WomenBy Anton Dotson, M.D.Testosterone and Aging:

The
connection between the testes and vigor has been known since the first written medical texts. Galen described the loss of
sexual drive, erectile function, and physical decline seen in castrated men. Ancient Greek texts prescribed the ingestion
of testicles to treat loss of energy and to enhance sexual performance. In the 1800's, physicians described beneficial responses
to testicular extracts, and even attempted testicular transplants. In 1935, testosterone purification became possible. The
physicians who accomplished this received the Nobel Prize in 1939. In 1940 and 1944, the first American published reports
of testosterone use for "the male climacteric" were published. The latter article was published in The Journal of the American
Medical Association.

From then until the 1970's, testosterone was given according to subjective criteria and
with generalized dosing regimens. Once testosterone levels could be measured, it became possible to more accurately assess
individual levels as an aid to implementing and precisely monitoring therapy. With the ability to measure testosterone came
data showing that testosterone levels decline with age. Studies found that after age 30, testosterone levels may decline an
average of 2% a year. This decline is a result of several concurrent changes. First is a decline in testosterone production
consistent with a decline in leydig cell (testosterone producing) number in the testes and decreasing activity of the enzymes
that produce testosterone. There is also a diminished response to pituitary signals that normally initiate testosterone production
and diminished coordination of the release of the pituitary signals that are produced, decreasing any chance for the testes
to continue a normal pattern of testosterone secretion. Finally, sex hormone-binding globulin (SHBG) levels increase with
age. These proteins "cling" to testosterone, so even though testosterone may be present, it is not "free" or biologically
available to do its work. Increasing SHBG levels, therefore, reduce free testosterone to a greater extent than the reduction
seen in total testosterone. Thus, less total testosterone production in conjunction with increasing binding protein levels
act in tandem to synergistically depress free/functional testosterone levels.

Testosterone is an anabolic (or
building) hormone. The age-related decline in testosterone levels is associated with the following identifiable signs or symptoms:

1.A decline in
muscle mass and strength. Loss of muscle volume and tensile strength are hallmarks of aging. Diminishing testosterone levels
directly correlate with a decrease in the synthesis rate of muscle proteins, formation of contractile structures, and the
force generating capabilities of muscle cells. Declines in muscle mass are also correlated with increased risk for falls and
fractures.

2.Increase in
body fat mass, particularly abdominal fat and pectoral fat. Sometimes, gynecomastia, (enlargement of breast tissue in men)
may occur. Decreases in testosterone are also associated with increasing levels of leptin. Leptin is a peptide hormone produced
by fat cells, and its circulating levels are directly reflective of an individual's fat mass. Adequate testosterone levels
and lean mass are inversely correlated with leptin levels.

3.Decrease of
bone mass. Studies indicate that age and associated declines in testosterone levels correlate with bone loss in men. Declines
in estradiol and testosterone levels are associated with bone loss in women as well, and this phenomenon appears at an earlier
age and at a more rapid rate compared to men. Up to 30% of men aged 60 and over may become osteoporotic. One in six will fracture
a hip at some point in his life. Women are hormonally and statistically more complex than men. Female hormone replacement
studies do not separate the effects of estrogens and testosterone, but do show benefits of proper overall hormone replacement
programs. An unsupplemented woman will, between age 60 and 80, show a 50% reduction in her original bone mineral density,
and one in four will suffer a vertebral or hip fracture.

5.Increased frequency
of erectile dysfunction in men, and diminished sexual response and pleasure in women.

6.Decreased sense
of overall wellbeing, perception of energy level, and vigor. These types of complaints, along with non-specific irritability,
are frequently the first symptoms associated with declining testosterone levels but are the most often overlooked or attributed
to stress or "not being as young as you used to be".

7.Decline in stamina
and exertional performance. A graph of the declines in testosterone and growth hormone levels can be placed over a graph of
the percentage of professional athletes still performing at a given age, with essentially identical shapes. Similar functional
declines are also frequently noted by other "performance-minded" individuals, like business executives and people whose careers
demand multi-tasking or complex problem solving skills.

9.Coronary artery
disease and cholesterol derangement. In population studies, low levels of testosterone are associated with increased risk
of atherosclerotic cardiac disease. Older men treated with testosterone can show decreases in total cholesterol and LDL (bad
cholesterol). Low testosterone levels are also correlated with a greater degree of atherosclerotic obstruction when coronary
artery disease is present.

The goal of Testosterone Replacement
Therapy is to minimize, prevent, or reverse the affects of our age related decline. The beneficial effects of attaining healthy
testosterone levels are seen for both men and women, and are essentially the inverse of the aforementioned list of problems.
(Of course, the goals for testosterone level are appropriately lower for women.)

Appropriate Testosterone Measures: While
the clinical indicators of testosterone decline may give a care provider a notion that an individual may be a candidate for
testosterone replacement, objective measures must be obtained to properly institute and manage therapy, and rule out and address
accompanying medical problems. To adequately measure testosterone levels, both total and free testosterone studies should
be evaluated. For males, a level of 260-1,000 ng/dL is given as the normal laboratory range from men aged 20-70. For females,
this range is 15-70 ng/dL. Free testosterone levels average approximately 2% of the total, 50-210 pg/ml for men, and 1-10pg/ml
for women. Free testosterone is the slightly more valuable of the two, as it reflects the amount of testosterone available
to perform useful work at any one moment.

The fifty-year span from age 20 through 70 with the same normal range
is not very useful. A decline of 70% from more youthful levels may produce many or all of the previously mentioned clinical
problems, yet is declared "within normal range". A more accurate approach would be to use the normal range seen from age 30-35
(approximately 700-900 ng/dL for men, and 50-70 ng/dL for women), and try to maintain these levels over time rather than let
them continue to decline.

The Cenegenics® approach is to arrest falling levels and prevent their decline from
the start. Testosterone levels can give us enough clinical information to make a decision as to whether or not replacement
is indicated, but ideally would take place in the context of other hormonal and laboratory studies as well. Prostate Specific
Antigen (PSA) measurement must accompany testosterone levels at the time of an initial evaluation in order to screen for any
pre-existing prostate disease, to direct any prerequisite work-up of elevated level that may be associated with prostate disease,
and to be used as a baseline for future program follow-up.

Other studies, such as thyroid hormones, growth hormone
(hGH), leutinizing hormone (LH), dehydroepiandrosterone (DHEA), blood count, lipid profiles, and other laboratory and metabolic
markers - such as body composition and bone density - all play roles in maximizing a Testosterone Replacement Program. Once
therapy is initiated, follow up levels for testosterone and some of these other markers must be monitored over time in order
to assure adequate safety and maximize utility.

Testosterone Therapy:

After the decision to augment
testosterone levels has been made, the next step is deciding on the proper means of delivery. There are several different
modes of testosterone delivery, but the best method varies from individual to individual, and is dependent upon several factors.
Optimally, a testosterone delivery method should be clinically effective in correcting the signs and symptoms of testosterone
decline and produce predictable and reproducible physiologic levels of testosterone and estradiol. Testosterone can be converted
to estradiol by an aromatase enzyme. This is a relevant concern in men because some men seem to have a much more hard-wired
connection between testosterone and estradiol, so any intervention that raises testosterone levels may concomitantly raise
Estradiol levels in an undesired fashion. With proper follow up of levels, this is easily identified and avoided. The raising
of serum levels of dihydrotestosterone (DHT) does not seem to be clinically important. DHT is the agent associated with male-pattern
baldness and prostate disease, and any tissue that picks up testosterone is able to convert it to DHT inside the cell, yielding
the benefits of DHT without requiring any certain serum level and avoiding potential side effects. Testosterone is available
directly in oral, injectable, topical, and implantable formulations; and may also be supplemented indirectly by the administration
of human chorionic gonadotropin, which stimulates testosterone production by the testes.

Oral testosterone and androgens
such as fluoxynesterone, methyltestosterone, oxandrolone, or danazol are available for clinical use, but are not appropriate
for long-term testosterone replacement therapy. Their use is specific for certain disorders and must be used with great caution
as they can cause an increase in liver enzymes, blockage of liver drainage pathways, direct liver damage, and even liver tumors.
They also dramatically raise serum LDL cholesterol, decrease HDL cholesterol, and have been associated with increased risk
of myocardial infarction and stroke. Testosterone undecanoate is a testosterone compound given in an oral base that is taken
up by the lymph ducts in the intestines and is able to bypass the liver, thus minimizing the typical side effects. It has,
however, a very short half life (or length of effect), has low and frequently variable bio-availability from dose to dose,
and is not currently approved by the FDA for use in America. At present, there are no recommended oral testosterone formulations.

One
oral preparation that is useful for helping normalize testosterone levels in women is DHEA. Men do not convert DHEA into meaningful
levels of testosterone, but women may. A frequent first step in improving testosterone levels in women is to optimize DHEA
levels and re-check testosterone after 5-7 weeks, then use that value as the definitive criteria for instituting testosterone
therapy.

The injectable form of testosterone is not associated with the above-mentioned undesirable effects of oral
androgen administration and is available in a formulation - testosterone cypionate - that allows a relatively long biological
effect time and typically requires a dosage interval of only once each week. This method requires an intramuscular self injection
but provides testosterone, as noted previously, for a relatively long period of time and is low in cost. Delivering testosterone
this way has a 100% success rate in providing usable hormone. We are able to precisely control the dosage of testosterone
administered and easily manage it by following levels over time. For men whose testicles are no longer able to produce testosterone
in meaningful amounts, this is the replacement therapy of choice.Testosterone pellets have also been developed that can
provide augmented serum testosterone levels for up to six months. However, these pellets require a surgical procedure for
implantation and removal, and once they are placed, do not allow a means for tailoring dosage based on an individual's response.

Testosterone
formulations are also available for topical placement. These formulations allow testosterone absorption through the skin.
This is the therapy of choice for raising testosterone levels in women. In our experience, there is only limited application
for this delivery system for men because this method produces supraphysiologic serum levels of DHT - as testosterone is absorbed
through the skin, 5 alpha-reductase converts much of the testosterone to DHT, raising circulating levels of DHT and increasing
the exposure of prostate and hair follicle cells to DHT rather than testosterone, which is not as active in these cells and
not as well taken up. All other target tissues can utilize DHT or testosterone, with no advantage claimed by elevating DHT
levels. Testosterone patches have also been associated with other minor disadvantages. These include: low obtainable maximum
serum testosterone levels, difficulties with the area of skin required to apply creams to achieve therapeutic levels in men,
and local skin reactions. Mild to moderate reactions occur in as many as 50% of men using some formulations of the skin patch,
which have been shown in studies to produce a 30-50% failure rate in clinical applications. The very small amounts of testosterone
crème required to raise testosterone levels in women have not been associated with these problems. Patches may seem more user
friendly compared to injections, but we have found their use limited due to the above concerns.

An interesting
new way of enhancing testosterone has been through the use of human chorionic gonadotropin (hCG). In the testosterone control
pathways, the pituitary gland releases a hormone called leutinizing hormone (LH). LH travels to the testicles and stimulates
the Leydig cells to synthesize and secrete testosterone. LH acts as a "thermostat" for testosterone control. As the testicles
produce testosterone, levels in circulation rise. Once these levels reach a certain point, the pituitary decreases secretion
of LH, and the signal to the testicles to produce testosterone is diminished. As testosterone production decreases, the pituitary
gland senses this decrease and resumes secretion of LH. An analogy would be the thermostat on a furnace with testosterone
being the temperature; higher testosterone turns off the thermostat, lower testosterone turns on the thermostat.

We
are now able to acquire and administer synthetic LH. HCG binds the same receptors and has the same binding affinity for these
receptors that LH does. Administration of HCG, therefore, can mimic the effect of LH and increase an individual's testosterone
production without directly administering testosterone. In men who still have a functional LH/testosterone control loop, this
way of raising testosterone is the most physiologic, and is not associated with testicular atrophy that can occasionally be
seen with direct testosterone administration. HCG can be administered daily in small doses via a subcutaneous injection, or
given twice weekly via the same route. While direct injection of testosterone has a 100% success rate, there is approximately
a 10-15% failure rate seen in individuals using HCG. With normal aging, the testicles will at some point stop responding to
the LH signal from the pituitary, this is usually associated with a rise in LH levels. An analogy for this would be to consider
LH level a sign of the pituitary's appetite for testosterone. The higher the LH level, the greater the appetite; so with many
men, as testosterone secretion declines, the LH level rises in response. In some men, this LH rise does not occur, and when
HCG therapy is undertaken, we have no other initial marker to use in deciding whether or not this therapy will be effective.
If testosterone levels do not rise as we follow a patient's program, we know the "disconnect" between the testicles and the
pituitary has occurred, and this is an indication that, for that individual, direct testosterone supplementation is the appropriate
route.

Monitoring Testosterone Replacement:

Once any testosterone intervention is initiated, adequate
and ongoing follow up is critical. Starting testosterone therapy is only the first step in a replacement program. Continued
monitoring is the hallmark of a truly safe and successful program. As mentioned previously, for some men, a rise in testosterone
produces an exaggerated rise in estradiol levels, if this occurs, it can blunt or negate the beneficial effects of testosterone
and may even produce breast enlargement (gynecomastia). If estradiol levels rise too high, it is important to recognize this
and adjust testosterone dose or implement therapy to block the conversion of testosterone to excess estradiol. It is also
important to follow other metabolic markers that may be associated with testosterone therapy. Hemoglobin and hematocrit may
rise with testosterone therapy and must be monitored over time as well. If testosterone levels are kept too high, we may see
derangement in cholesterol metabolism and fluid retention, potentially exacerbating high blood pressure or causing edema.
Overly elevated testosterone levels may also hasten the onset of prostatic hyperplasia. Following laboratory markers over
time and adjusting therapy appropriately is a prerequisite for an efficacious and safe testosterone replacement program.

Conclusion:

Testosterone
levels fall with age, free testosterone to a greater extent than total testosterone. Testosterone levels are directly related
to a number of age-related changes: notably muscle strength, cognitive function, body composition, and overall self perception
of energy and vigor. Testosterone replacement therapy enhances muscle strength and lean body mass, decreases leptin, and may
enhance cognitive function, bone mineral density, and have positive effects on the cardiovascular system. Testosterone can
be easily administered and monitored as part of a complete proactive health program.

Serum levels of TTT

from Goodman & Gilman, pharmocology textbook

Gel shown to deliver more testosterone than the pattch. 100 mg/daily is better than 50.
The first graph is of the enanthate form of TTT. It is orally active, but with prolonged usage causes liver damage.--jk